Cholinergic efferent synaptic transmission regulates the maturation of auditory hair cell ribbon synapses

Johnson, Stuart L.; Wedemeyer, Carolina; Vetter, Douglas E.; Adachi, Roberto; Holley, Matthew C.; Elgoyhen, Ana Belén; Marcotti, Walter

doi:10.1098/rsob.130163

Cited by 54 publications

(52 citation statements)

References 48 publications

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“…), which is abundantly expressed in the cochlea (Johnson et al . ), in auditory brainstem neurons (Moritz et al . ) and also in the calyx of Held (Young & Neher, ; Luo & Sudhof, ).…”

Section: Discussionmentioning

confidence: 99%

“…As a neuropeptide of a very small size, UCN3 is packed into dense core vesicles (van den Pol, 2012) and can then be released by either kiss-and-run or full fusion depending on the form of stimulation (Zhang et al 2011). The sensor of activity levels which decides the mode of vesicle fusion is suggested to be synaptotagmin (Zhang et al 2011), which is abundantly expressed in the cochlea (Johnson et al 2013), in auditory brainstem neurons (Moritz et al 2015) and also in the calyx of Held (Young & Neher, 2009;Luo & Sudhof, 2017). In future studies we will target the physiology of this receptor system in the auditory pathway to reveal the cellular mechanisms underlying the effects of UCN3 on stress recovery described in the present study.…”

Section: Cellular Mechanisms Of Ucn3 Signallingmentioning

confidence: 99%

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Urocortin 3 signalling in the auditory brainstem aids recovery of hearing after reversible noise‐induced threshold shift

Fischl

Ueberfuhr

Drexl³

et al. 2019

The Journal of Physiology

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Key points Ongoing, moderate noise exposure does not instantly damage the auditory system but may cause lasting deficits, such as elevated thresholds and accelerated ageing of the auditory system.The neuromodulatory peptide urocortin‐3 (UCN3) is involved in the body's recovery from a stress response, and is also expressed in the cochlea and the auditory brainstem.Lack of UCN3 facilitates age‐induced hearing loss and causes permanently elevated auditory thresholds following a single 2 h noise exposure at moderate intensities.Outer hair cell function in mice lacking UCN3 is unaffected, so that the observed auditory deficits are most likely due to inner hair cell function or central mechanisms.Highly specific, rather than ubiquitous, expression of UCN3 in the brain renders it a promising candidate for designing drugs to ameliorate stress‐related auditory deficits, including recovery from acoustic trauma. AbstractEnvironmental acoustic noise is omnipresent in our modern society, with sound levels that are considered non‐damaging still causing long‐lasting or permanent changes in the auditory system. The small neuromodulatory peptide urocortin‐3 (UCN3) is the endogenous ligand for corticotropin‐releasing factor receptor type 2 and together they are known to play an important role in stress recovery. UCN3 expression has been observed in the auditory brainstem, but its role remains unclear. Here we describe the detailed distribution of UCN3 expression in the murine auditory brainstem and provide evidence that UCN3 is expressed in the synaptic region of inner hair cells in the cochlea. We also show that mice with deficient UCN3 signalling experience premature ageing of the auditory system starting at an age of 4.7 months with significantly elevated thresholds of auditory brainstem responses (ABRs) compared to age‐matched wild‐type mice. Following a single, 2 h exposure to moderate (84 or 94 dB SPL) noise, UCN3‐deficient mice exhibited significantly larger shifts in ABR thresholds combined with maladaptive recovery. In wild‐type mice, the same noise exposure did not cause lasting changes to auditory thresholds. The presence of UCN3‐expressing neurons throughout the auditory brainstem and the predisposition to hearing loss caused by preventing its normal expression suggests UCN3 as an important neuromodulatory peptide in the auditory system's response to loud sounds.

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“…), which is abundantly expressed in the cochlea (Johnson et al . ), in auditory brainstem neurons (Moritz et al . ) and also in the calyx of Held (Young & Neher, ; Luo & Sudhof, ).…”

Section: Discussionmentioning

confidence: 99%

Section: Cellular Mechanisms Of Ucn3 Signallingmentioning

confidence: 99%

Urocortin 3 signalling in the auditory brainstem aids recovery of hearing after reversible noise‐induced threshold shift

Fischl

Ueberfuhr

Drexl³

et al. 2019

The Journal of Physiology

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“…; Johnson et al . b ). Taken together, these mechanisms generate a topographically specific firing pattern necessary for maturation of the synaptic machinery of IHC ribbon synapses before hearing onset (Johnson et al .…”

Section: Discussionmentioning

confidence: 99%

Tonotopic action potential tuning of maturing auditory neurons through endogenous ATP

Jovanovic

Radulović

Coddou

et al. 2016

The Journal of Physiology

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Synaptic refinement and strengthening are activity-dependent processes that establish orderly arranged cochleotopic maps throughout the central auditory system. The maturation of auditory brainstem circuits is guided by action potentials (APs) arising from the inner hair cells in the developing cochlea. The AP firing of developing central auditory neurons can be modulated by paracrine ATP signalling, as shown for the cochlear nucleus bushy cells and principal neurons in the medial nucleus of the trapezoid body. However, it is not clear whether neuronal activity may be specifically regulated with respect to the nuclear tonotopic position (i.e. sound frequency selectivity). Using slice recordings before hearing onset and in vivo recordings with iontophoretic drug applications after hearing onset, we show that cell-specific purinergic modulation follows a precise tonotopic pattern in the ventral cochlear nucleus of developing gerbils. In high-frequency regions, ATP responsiveness diminished before hearing onset. In low-to-mid frequency regions, ATP modulation persisted after hearing onset in a subset of low-frequency bushy cells (characteristic frequency< 10 kHz). Down-regulation of P2X2/3R currents along the tonotopic axis occurs simultaneously with an increase in AMPA receptor currents, thus suggesting a high-to-low frequency maturation pattern. Facilitated AP generation, measured as higher firing frequency, shorter EPSP-AP delay in vivo, and shorter AP latency in slice experiments, is consistent with increased synaptic efficacy caused by ATP. Finally, by combining recordings and pharmacology in vivo, in slices, and in human embryonic kidney 293 cells, it was shown that the long lasting change in intrinsic neuronal excitability is mediated by the P2X2/3R.

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“…Consistent with this model, activation of acetylcholine receptors in acutely isolated cochleae caused IHCs to switch from sustained to burst firing ( Johnson et al, 2011 ). However, in vivo recordings from auditory brainstem revealed that neuronal burst firing remains, with altered features, in α9 knockout mice ( Clause et al, 2014 ), which lack functional efferent signaling in IHCs ( Johnson et al, 2013 ), and persists in IHCs and auditory neurons in cochleae maintained in vitro without functional efferents ( Johnson et al, 2013 ). Thus, cholinergic efferents appear to modulate the temporal characteristics of bursts, but are not essential to initiate each event.…”

Section: Introductionmentioning

confidence: 99%

Purinergic signaling in cochlear supporting cells reduces hair cell excitability by increasing the extracellular space

Babola

Kersbergen

Wang

et al. 2019

Preprint

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Neurons in developing sensory pathways exhibit spontaneous bursts of electrical 11 activity that are critical for survival, maturation and circuit refinement. In the auditory system, 12 intrinsically generated activity arises within the cochlea, but the molecular mechanisms that 13 initiate this activity remain poorly understood. We show that burst firing of mouse inner hair cells 14 prior to hearing onset requires P2RY1 autoreceptors expressed by inner supporting cells. P2RY1 15 activation triggers K + efflux and depolarization of hair cells, as well as osmotic shrinkage of 16 supporting cells that dramatically increased the extracellular space and speed of K + 17 redistribution. Pharmacological inhibition or genetic disruption of P2RY1 suppressed neuronal 18 burst firing by reducing K + release, but unexpectedly enhanced their tonic firing, as water 19 resorption by supporting cells reduced the extracellular space, slowing K + clearance. These 20 studies indicate that purinergic signaling in supporting cells regulates hair cell excitability by 21 controlling the volume of the extracellular space. 22 23 Introduction 24The developing nervous system must generate, organize, and refine billions of neurons and their 25 connections. While molecular guidance cues forge globally precise neuronal connections between 26 distant brain areas (Stoeckli, 2018; Dickson, 2002), the organization of local connections is initially 27 coarse and imprecise (Dhande et al., 2011; Kirkby et al., 2013; Sretavan and Shatz, 1986). Coinci-28 dent with the refinement of topographic maps, nascent circuits experience bursts of intrinsically 29 generated activity that emerge before sensory systems are fully functional (Kirkby et al., 2013). 30 This intrinsically generated activity consists of periodic bursts of high frequency firing that pro-31 motes the survival and maturation of neurons in sensory pathways (Blankenship and Feller, 2010; 32 Moody and Bosma, 2005). The precise patterning of this electrical activity appears crucial for re-33 finement of local connections, as its disruption results in improper formation of topographic maps 34 (Antón-Bolaños et al., 2019; Burbridge et al., 2014; Xu et al., 2011) and impaired maturation and 35 specification of sensory neurons (Shrestha et al., 2018; Sun et al., 2018). In all sensory systems 36that have been examined, spontaneous burst firing arises within their respective developing sen-37 sory organs, e.g. retina, olfactory bulb, spindle organ, and cochlea (Blankenship and Feller, 2010). 38 Although the mechanisms that induce spontaneous activity in the developing retina have been ex-39 1 of 26 Manuscript submitted to eLife tensively explored, much less is known about the key steps involved in triggering auditory neuron 40 burst firing in the developing cochlea. Understanding these processes may provide novel insights 41 into the causes of developmental auditory disorders, such as hypersensitivity to sounds and audi-42 tory processing disorders that prevent children from communicating a...

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Cholinergic efferent synaptic transmission regulates the maturation of auditory hair cell ribbon synapses

Cited by 54 publications

References 48 publications

Urocortin 3 signalling in the auditory brainstem aids recovery of hearing after reversible noise‐induced threshold shift

Urocortin 3 signalling in the auditory brainstem aids recovery of hearing after reversible noise‐induced threshold shift

Tonotopic action potential tuning of maturing auditory neurons through endogenous ATP

Purinergic signaling in cochlear supporting cells reduces hair cell excitability by increasing the extracellular space

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